Title: Metabolic Interventions for Enhancing Cognitive Resilience in Aging and Alzheimer's Disease Abstract: By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million, occupying a larger portion of our population aging demographics than ever recorded in history. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, a large proportion of elderly people experience memory loss or other types cognitive decline that interfere with quality of life. To date, therapeutic options for mitigating cognitive dysfunction in aging and Alzheimer's disease are limited. A barrier to advancing treatments for cognitive loss in aging it that the brain regions critical for higher cognition show distinct neurobiological mechanisms of dysfunction in old age. One factor that changes ubiquitously across the brain in old age, however, is a reduced ability to use glucose for energy production. The long-term goal of this research program is the implementation of metabolic-based therapies for enhancing cognitive resilience in old age and Alzheimer's disease. The primary objective of this proposal is to investigate the mechanisms by which ketogenic diets restore energy metabolism across the brain to improve cognition in pre-clinical models of aging and Alzheimer's disease. Based on our preliminary data, we will test the central hypothesis that elevated ketone body levels will normalize activity across the prefrontal cortex and medial temporal lobe, and attenuate the progression of tau pathology in a rat model pre-clinical Alzheimer's disease. This hypothesis will be testing with the following specific aims: 1) Determine if a ketogenic diet improves cognition by restoring medial temporal lobe and prefrontal cortical network dynamics in aged rats, 2) Determine biochemical mechanisms of enhanced cognition in aged rats by a ketogenic diet, and 3) Determine the interaction between nutritional ketosis and Alzheimer's disease tau pathology. The proposed research is innovative because behavioral data from a task that is comparable to multi-tasking in humans, will be integrated with cellular imaging and biochemical analysis to test a metabolic intervention in both male and female rats. The rationale for this research is that improving brain energy metabolism may be a mechanism for globally optimizing brain circuits to alleviate cognitive aging. The significance of the successful completion of this work will be the development of broad therapeutic strategies for treating both age- and disease-related cognitive decline.